A nanosized food-grade quercetin-loaded nanoemulsion (QNE) system comprising capmul MCM NF (oil) and cremophor RH 40 (surfactant) was developed using a high-speed homogenization technique. The developed QNE was studied for its significant neuroprotective (anti-Parkinsonism) and cytotoxicity (anticancer) effects against Caenorhabditis elegans (C. elegans) strains and human cancer cells, respectively. HR-TEM studies revealed that the QNE was spherical with a mean globule size of ~50 nm. Selected area electron diffraction (SAED) studies results demonstrated that QNE was amorphous. In vivo results show that QNE potentially reduced the α-Syn aggregation, increased mitochondrial and fat content, and improved the lifespan in transgenic C. elegans strain NL5901. QNE significantly downregulated the reactive oxygen species (ROS) levels in wild-type C. elegans strain N2. In vitro results of the MTT assay show that QNE significantly exhibited chemotherapeutic effects in all treated human cancer cells in an order of cytotoxicity: HeLa cells > A549 cells > MIA PaCa-2 cells, based on the IC50 values at 24 h. Conclusively, the QNE showed improved solubility, targetability, and neuroprotective effects against the PD-induced C. elegans model, and also cytotoxicity against human cancer cells and could be potentially used as an anti-Parkinson’s or anticancer agent.
The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis where only Arg244His (not null) worms elevate lactate/pyruvate levels, pointing to a missense-induced, ‘Warburg’-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesise that Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach may illuminate wider SDH pathology.
Cellular homeostasis is maintained by rapid and systematic cleansing of aberrant and aggregated proteins within cells. Neurodegenerative diseases (NDs) especially Parkinson's and Alzheimer's disease are known to be associated with multiple factors, most important being impaired clearance of aggregates, resulting in the accumulation of specific aggregated protein in the brain. Protein quality control (PQC) of proteostasis network comprises proteolytic machineries and chaperones along with their regulators to ensure precise operation and maintenance of proteostasis. Such regulatory factors coordinate among each other multiple functional aspects related to proteins, including their synthesis, folding, transport, and degradation. During aging due to inevitable endogenous and external stresses, sustaining a proteome balance is a challenging task. Such stresses decline the capacity of the proteostasis network compromising the proteome integrity, affecting the fundamental physiological processes including reproductive fitness of the organism. This review focuses on highlighting proteome-wide changes during aging and the strategies for proteostasis improvements. The possibility of augmenting the proteostasis network either via genetic or pharmacological interventions may be a promising strategy towards delaying age-associated pathological consequences due to proteome disbalance, thus promoting healthy aging and prolonged longevity.
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